Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Cytoprotection”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 37 records · Page 2Linked to original sources
PubMed1995

Adaptive cytoprotection in cultured rat gastric mucus-producing cells. Role of mucus and prostaglandin synthesis.

In cultured gastric mucosal cells, we investigated whether: (1) adaptive cytoprotection was associated with stimulation of endogenous prostaglandin synthesis; (2) prostaglandins given exogenously were cytoprotective against ethanol-induced gastric mucosal cell damage; and (3) a relationship existed between cytoprotection and mucus release. Cytolysis was quantified by measuring 51Cr release from prelabeled cells. Mucus release was determined by measurement of [3H]glucosamine release. Concentrations of ethanol > 12% caused cell damage and increased 51Cr release dose dependently. Pretreatment with low concentrations of ethanol (0.5-1.5%) decreased ethanol-induced 51Cr release, but also decreased prostaglandin E2 synthesis. Prostaglandin E2 and 16,16-dimethyl prostaglandin E2 given exogenously were cytoprotective against ethanol-induced gastric mucosal cell damage. Treatment with low concentrations of ethanol (1.5%) increased mucus release from cultured gastric mucosal cells. However, prostaglandin E2 and 16,16-dimethyl prostaglandin E2 did not affect mucus release. We conclude that in cultured gastric mucus-producing cells: (1) adaptive cytoprotection occurs without stimulation of endogenous prostaglandin synthesis but with increase in mucus release; and (2) exogenous prostaglandins are cytoprotective against ethanol-induced gastric mucosal cell damage without stimulating mucus release in vitro. We postulate that adaptive cytoprotection in cultured gastric mucus-producing cells is not mediated by prostaglandin, but by mucus released in response to a mild irritant.

16,16-Dimethylprostaglandin E2↗
PubMed2003

Antioxidant and cytoprotective activity of indole derivatives related to melatonin.

Melatonin (MLT) is known for its radical scavenger activity, which had been related to its ability to protect neuronal cells from different kinds of oxidative stress. In particular, MLT protects rat cerebellum granular cells from kainate-induced necrosis at concentrations higher than 100 microM, and is able to reduce lipoperoxidation induced by radical stress in rat brain homogenate at similar concentrations. On the other hand, MLT has nanomolar affinity for its membrane receptors (MT1 and MT2), and these are completely saturated at the high concentrations employed when the cytoprotective effect is observed. Other indole derivatives are also known to possess antioxidant and cytoprotective activity. In order to dissociate the cytoprotective effect of MLT from its receptor affinity, and to investigate the structure-activity relationships (SAR) between this effect and some potentially relevant chemical properties, we prepared a series of indole derivatives, where the structure of MLT was gradually modulated, varying the 5-methoxy group nature and position, the acylaminoethyl chain position, and by the introduction of lipophilic groups. These modifications resulted in a set of compounds having different receptor affinity and intrinsic activity, different lipophilicity, and different substitution at the indole nucleus. The compounds were tested for their antioxidant potency by the ABTS test and by inhibition of rat brain homogenate lipoperoxidation; their cytoprotective effect was also estimated from the inhibition of kainate-induced cellular death on rat cerebellum granular cells, and the results were evaluated by SAR comparison and QSAR analysis. An isomer of MLT resulted more potent and effective than MLT itself in the cytoprotection test, although it showed similar potency in the peroxidation test, and it was devoid of the ability to stimulate MT1 and MT2 receptors. This compound was selected as the lead compound for a further SAR study, devoted to the optimization of the cytoprotective effect and to the investigation on its mechanism.

Animals↗
PubMed2003

In vitro cytoprotective activity of squalene on a bone marrow versus neuroblastoma model of cisplatin-induced toxicity. implications in cancer chemotherapy.

The development of a non-toxic selective cytoprotective agent that preferentially protects normal tissues from chemotherapy toxicity, without protecting malignant tissues, is a major challenge in cancer chemotherapy research. The available cytoprotective agents are either toxic or lack selective cytoprotective activity. Here, we report the in vitro selective cytoprotective activity of squalene, an isoprenoid molecule with antioxidant properties. Normal human bone marrow (BM) derived colony-forming unit (CFU) growth was increased by squalene in a dose-dependent manner. Squalene (12.5-25 microM) treatment significantly protected the CFUs from cisplatin-induced toxicity; the protective effect was equivalent to reduced glutathione (GSH), a known cytoprotective agent. Squalene also increased the long-term survival of cisplatin-treated 4-week-old CFUs. Cisplatin-induced apoptosis of CFUs as measured by the TUNEL assay was reduced by squalene. To examine the squalene-induced protection of tumours, several neuroblastoma cell lines, including five MYCN-amplified cell lines, were grown in monolayers, as well as in anchorage-independent cultures, in the presence of squalene and cisplatin. Squalene did not protect the neuroblastoma (NBL) cell lines from cisplatin-induced toxicity. In addition, squalene did not protect the NBL cells from carboplatin, cyclophosphamide, etoposide and doxorubicin-induced toxicity. In conclusion, our results suggest that squalene has a selective in vitro cytoprotective effect on BM-derived haematopoietic stem cells that is equipotent to GSH.

Antineoplastic Agents↗
PubMed2006

Induction of Hsp 70 in Vero cells in response to mycotoxins cytoprotection by sub-lethal heat shock and by Vitamin E.

This paper analysed the toxicity mechanisms of several mycotoxins using Hsp 70 expression, cytoprotection of Vero cells by sub-lethal heat shock (sub-LHS) and Vitamin E. Our aim was (i) to determine whether Citrinin (CTN), Zearalenone (ZEN) and T2 toxin (T2) could induce the expression of Hsp 70, (ii) to check whether or not elevated levels of Hsp and Vitamin E pre-treatment could provide cytoprotection from these mycotoxins, and finally (iii) to emphasize the eventual involvement of oxidative stress on mycotoxin's toxicity. Our study demonstrated that the three examined mycotoxins induced Hsp 70 expression in a dose-dependent manner. A cytoprotective effect of Hsp 70 was obtained when Vero cells were exposed to sub-lethal heat shock followed by a 12h recovery prior to mycotoxins treatment and evidenced by a reduction of their cytolethality. This cytoprotection suggested that Hsp 70 might constitute an important cellular defence mechanism. A cytoprotective action was also obtained although at lesser extent, when cells were pre-treated with an antioxidant agent, the Vitamin E before mycotoxins treatment. This Vitamin E cytoprotection evoked the involvement of oxidative stress in mycotoxins induced toxicity, which was further, confirmed by the reduction of Hsp 70 expression when cells were pre-treated with Vitamin E prior to mycotoxins. Our data clearly shows that oxidative stress is certainly involved in the toxicity of the three studied mycotoxins, Citrinin, Zearalenone and T2 toxin and may therefore constitutes a relevant part in their toxicities; however, at variable extent from one mycotoxin to another.

Animals↗
PubMed2003

Nitric oxide-mediated cytoprotection of hepatocytes from glucose deprivation-induced cytotoxicity: involvement of heme oxygenase-1.

Heme oxygenase-1 (HO-1) is the rate-limiting enzyme in heme catabolism, which leads to the generation of carbon monoxide (CO), biliverdin, and free iron. One of 3 mammalian HO isoforms, HO-1, is a stress-responsive protein and known to modulate such cellular functions as cytokine production, cell proliferation, and apoptosis to protect organs and tissues from acute injury. Although nitric oxide (NO)-mediated cytoprotective effects against cytotoxicity induced by glucose deprivation have been well recognized, the underlying mechanisms remain to be elucidated. Thus, we investigate the involvement of HO-1 in the cytoprotective effects of NO. Deprivation of glucose markedly reduced the viability of BNL CL.2 cells and primary rat hepatocytes. Pretreatment with NO donor, sodium nitroprusside (SNP), protected hepatocytes from glucose deprivation-induced cytotoxicity; zinc protoporphyrin (ZnPP) IX, an inhibitor of HO, was found to block the SNP-induced cytoprotection. SNP increased the induction of HO-1 protein as well as its activity in hepatocytes. A cytoprotective effect comparable to SNP was observed when the cells were transfected with HO-1 gene or preincubated with another HO-1 inducer, hemin. Additional experiments revealed the involvement of CO in the cytoprotective effect of SNP/HO-1 in BNL CL.2 cells. CO mediated cytoprotective effect through suppression of ERK MAPK activation. In conclusion, our results show that SNP protects hepatocytes from glucose deprivation-induced cytotoxicity through up-regulation of HO-1. Thus, HO-1 might be an important cellular target of NO donor with clinical implications for the prevention of acute liver injury in several pathological conditions.

Animals↗
PubMed2004

Grp78 is essential for 11-deoxy-16,16-dimethyl PGE2-mediated cytoprotection in renal epithelial cells.

11-Deoxy-16,16-dimethyl PGE(2) (DDM-PGE(2)) protects renal proximal tubule epithelial cells (LLC-PK(1)) against the toxicity induced by 2,3,5-tris(glutathion-S-yl)hydroquinone (TGHQ), a potent nephrotoxic and nephrocarcinogenic metabolite of hydroquinone. We have now determined the ability of DDM-PGE(2) to protect against other renal toxicants and report that DDM-PGE(2) only protects against oncotic cell death, induced by H(2)O(2), iodoacetamide, and TGHQ, but not against apoptotic cell death induced by cisplatin, mercuric chloride, or tumor necrosis factor-alpha. DDM-PGE(2)-mediated cytoprotection is associated with the upregulation of at least five proteins, including the major endoplasmic reticulum (ER) chaperone glucose-regulated protein 78 (Grp78). To elucidate the role of Grp78 in oncotic cell death, we used LLC-PK(1) cells in which induction of grp78 expression was disrupted by stable expression of an antisense grp78 RNA (pkASgrp78). As anticipated, DDM-PGE(2) failed to induce Grp78 in pkASgrp78 cells, with a concomitant inability to provide cytoprotection. In contrast, DDM-PGE(2) induced Grp78 and afforded cytoprotection against H(2)O(2), iodoacetamide, and TGHQ in empty vector transfected cells (pkNEO). These data suggest that Grp78 plays an essential role in DDM-PGE(2)-mediated cytoprotection. Moreover, TGHQ-induced p38 MAPK activation is disrupted under conditions of a compromised ER stress response in pkASgrp78 cells, which likely contributes to the loss of cytoprotection. Finally, using two-dimensional gel electrophoresis coupled to matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy, we found that DDM-PGE(2) induced several proteins in pkNEO cells, but not in pkASgrp78 cells, including retinol-binding protein, myosin light chain, and heat shock protein 27. The findings suggest that additional proteins may act in concert with Grp78 during DDM-PGE(2)-mediated cytoprotection against oncotic cell death.

Animals↗
PubMedDate not supplied

Examination of the mechanisms of action of diverse cytoprotectants in renal cell death.

Glycine, strychnine, muscimol, allopregnanolone, and pregnenolone sulfate act in the late phase of renal cell injury, block Cl- influx and cell lysis induced by the mitochondrial inhibitor antimycin A, and promote the recovery of respiration and ion transport following hypoxia/reoxygenation. However, the mechanism of action of these compounds has not been completely elucidated. Recently, we have shown that calpains are critical mediators of renal cell death produced by diverse toxicants and that antimycin A exposure results in calpain translocation from the cytosol to the membrane fraction that is temporally associated with Cl- influx and precedes cell death/lysis. The current study examined the effects of a group of diverse cytoprotectants on calpain activity and determined if calpain inhibition plays a role in the cytoprotection produced by these compounds. The cytoprotection produced by glycine, strychnine, muscimol, allopregnanolone, and pregnenolone sulfate in rabbit renal proximal tubules exposed to antimycin A was associated with the inhibition of antimycin A-induced calpain translocation. None of the cytoprotectants had a direct effect on calpain activity. All of the cytoprotectants decreased calcium-ionophore-induced cell death. Glycine, strychnine, and muscimol also blocked antimycin A mediated extracellular Ca2+ influx. These data suggest that the cytoprotective mechanism of action of glycine, strychnine, and muscimol involves the inhibition of antimycin A mediated extracellular Ca2+ influx as well as calpain translocation and associated Cl- influx. In contrast, the mechanism of action of the neurosteroids results only from the blockade of calpain translocation and associated Cl- influx.

Animals↗
PubMed1986

Direct and adaptive cytoprotection.

Cytoprotection confers increased cellular resistance to various damaging challenges. For example, the administration of certain prostaglandins (PG) prevents injury or facilitates recovery from injury in tissues exposed to noxious substances, such as ethanol, aspirin, and indomethacin. In addition, naturally occurring PG (E and I types) may play a physiological role in protecting the gastroduodenal mucosa against corrosion by gastric juice. Within a responsive tissue, not all cells may be protected by PG against severe damage. Thus, while PG will not prevent necrosis of the gastric epithelial monolayer during exposure to 100% ethanol, it does protect the deeper gastric cells of the mucosa from destruction. Cytoprotection of the gastroduodenal mucosa is independent of the antisecretory activity of PG. The ED100 cytoprotective dose of a prostaglandin may be less than 1% of the ED50 antisecretory dose of the same agent, and some cytoprotective prostaglandins are not antisecretory in some animal models. The best of the proposed mechanisms to account for cytoprotection include stimulation of mucus or HCO3 secretion, and mucosal vasodilation. However, there are no definitive data to substantiate these hypotheses and, in fact, evidence does exist to disprove each theory. Gastric mucosal exposure to mildly damaging concentrations of an agent will increase mucosal resistance to subsequent exposure to a much greater and more damaging concentration of the same agent. This "adaptive cytoprotection" can be abolished by indomethacin, an inhibitor of endogenous prostaglandin synthesis.

Adaptation, Physiological↗
PubMed1990

Putative mechanisms of cytoprotective effect of certain antacids and sucralfate.

An investigation of cytoprotective activity of certain antacids and inert particles was carried out by treating ethanol-induced gastric mucosal damage in rats in order to clarify possible mechanisms by which aluminum-containing antacids act. Al(OH)3 inhibited gastric mucosal damage in a dose-related and time-dependent manner. Neither aluminum ions themselves nor the particle size of the Al(OH)3 complex were responsible for the observed cytoprotection, since neither AlCl3, chemically inert Al2O3*C, nor sea sand showed protective effects. Hyperosmolality in the gastric lumen was not a deciding factor in inducing cytoprotection. Silicic acid and titanium dioxide, with superficial charge similar to Al(OH)3 proved to be effective in inhibiting gastric hemorrhagic lesions and releasing PGE2, suggesting that the surface charge of Al(OH)3 may be important in its cytoprotective properties. The same may also be valid for sucralfate. Since antacid-induced cytoprotection was only partly reduced by pretreatment with indomethacin, it is likely that additional mechanisms and mediators other than prostaglandins, such as nonprotein sulfhydryls, also are involved in gastric cytoprotection arising from aluminum-containing antacids.

Aluminum Hydroxide↗
PubMed2001

Non-steroidal anti-inflammatory and cytoprotective drug co-prescription in general practice. A general practitioner-based survey in France.

BACKGROUND AND AIM: Non-steroidal anti-inflammatory drugs (NSAIDs) represent one of the most frequently prescribed drugs. Gastrointestinal damage, the most common side effect of NSAIDs. can be limited by the prescription of cytoprotective agents. In order to assess determinants of NSAID-associated cytoprotective agent prescriptions in primary care practice, we performed a general practitioner (GP)-based study. METHODS: After a 2-month intensive information campaign, the participation of all GPs of the Côte d'Or (France) administrative area was requested. During a 2-month period, GPs had to return a mailed questionnaire on NSAID prescription for up to ten consecutive patients aged over 18 years who required NSAIDs. This 30-item questionnaire included questions about the patient, the type of NSAID and the GP. RESULTS: GP participation rate was 24%, and 791 prescriptions were provided. GPs who participated in the study were representative of GPs of the area in terms of sex, time elapsed since graduation and GP practice area. Around 80% of the patients included in the study were under the age of 65 years. The proportion of prescriptions combining NSAIDs and gastroprotective agents was 29.5%. Omeprazole accounted for 58% of the coprescriptions and misoprostol for 29%. Independent determinants associated with the co-prescription of a cytoprotective agent were age [odds ratio (OR) 4.1; confidence interval (CI) 95% 2.3 7.4], previous history of poor NSAID tolerance (OR 10.4; CI 95% 5.8-18.6), previous history of moderate to severe digestive disorders (OR 13.4; CI 95% 5.1 35.4) and indication for chronic illness (OR 1.8, CI 95% 1.1-3.1). Prescriptions of cytoprotective drugs were in conformity with official guidelines for 78.3% of the patients. Although around 60% of the patients with risk factors for poor tolerance received a gastroprotective drug, 50% of the patients over 65 years did not receive it. Conversely, nearly 12% of the patients with no risk factors were prescribed cytoprotective agents. Patient history was the main reason put forward by GPs for prescribing cytoprotective drugs. CONCLUSION: Although a large majority of GP prescriptions were in accordance with official recommendations, inadequate NSAID prescription practices remain relatively frequent especially with regard to the elderly.

Adult↗
PubMed1985

Ulcer formation and cytoprotection by acetazolamide.

Acetazolamide, a carbonic anhydrase inhibitor, was administered orally and subcutaneously to rats. Acetazolamide increased the gastric ulcerogenicity of indomethacin, but inhibited gastric ulcers produced by acidified aspirin. When administered alone to fasted rats, it did not produce gastric ulcers. Acetazolamide was also cytoprotective for the stomach (it reduced dose dependently the number of gastric necrotic lesions caused by absolute ethanol given orally) and for the small intestine (it prevented dose dependently intestinal lesions produced by administration of a high dose of indomethacin). Acetazolamide did not prevent the antiulcer effect of PGE2 (against aspirin-induced ulcers) nor the cytoprotective effect of 16,16-dimethyl PGE2 (against ethanol-induced gastric lesions). The degree of gastric cytoprotection increased with time after a single administration of acetazolamide; the optimal effect occurred 60 and 90 min after oral and subcutaneous administration, respectively. Pretreatment with indomethacin completely prevented the cytoprotective effect of acetazolamide; this suggests that the cytoprotective effect may be mediated by endogenous release of prostaglandins by the stomach. All the effects of acetazolamide reported here were observed after either oral or subcutaneous administration. The mechanism by which acetazolamide influences ulcer formation and is cytoprotective is unknown.

16,16-Dimethylprostaglandin E2↗
PubMed1993

Antisecretory and cytoprotective doses of enprostil do not alter gastric mucosal blood flow.

Prostaglandins of the E series are antisecretory and cytoprotective. Cytoprotection occurs in the deep but not superficial gastric mucosa. It has been hypothesized that the mechanism of cytoprotection involves increased gastric mucosal blood flow (GMBF). However, basal and stimulated gastric mucosal blood flow is greater in the deep than superficial corpus mucosa. The purpose of this study was to investigate the effect of a prostaglandin E2 analog, enprostil, on GMBF in the deep mucosa, where cytoprotection is observed, in both antisecretory and cytoprotective doses. Gastric mucosal blood flow in the deep half of the mucosa was measured by the hydrogen gas clearance method before, during and after intragastric perfusion of enprostil, 0.1-100 micrograms/kg, in urethane anesthetized rats. Enprostil did not alter GMBF in any of the doses tested. Therefore, the cytoprotective action of enprostil is mediated by factors other than a primary increase in GMBF.

Analysis of Variance↗
PubMed2004

Cytoprotection by Achyrocline satureioides (Lam) D.C. and some of its main flavonoids against oxidative stress.

Epidemiological studies indicate that dietary antioxidants can influence the incidence of neurodegenerative diseases. Among them flavonoids have been proposed to be effective cytoprotectors. Consequently, herbs with a high concentration of these compounds such as Achyrocline satureioides, Ginkgo biloba and Epilobium parviflorum are of special interest. In this context a comparative study of the cytoprotective capacity of infusions from the three plants against an oxidative insult was performed. Hence, the cytoprotective activity of each infusion against H2O2 injury to PC12 cells was tested and the antioxidant capacity was assessed by the ABTS*+ radical bleaching assay. Free and glycosylated flavonoids contained in the infusions were identified by HPLC and the cytoprotective effect of some of these individual flavonoids was tested. The analysis of the flavonoid content of the infusions revealed different profiles. Epilobium parviflorum infusion showed the highest antioxidant capacity but only Achyrocline satureioides infusion proved to be cytoprotective. Moreover, the free flavonoids quercetin and luteolin contained in this infusion were also cytoprotective. In conclusion, the free radical scavenger capacity did not correlate with the cytoprotective profile of the infusions. The special mixture of unglycosylated Achyrocline satureioides flavonoids could be a clue to explain the unique effect of this plant.

Achyrocline↗
PubMed2006

Comparison of rapamycin versus FK506 on expression of cytoprotective genes in the rat kidney allografts undergoing chronic allograft nephropathy.

AIMS: It is increasingly recognized that expression of cytoprotective genes in grafts can affect the progress of chronic allograft nephropathy (CAN). Little is known about the influence of different immunosuppressive regimens on expression of cytoprotective genes in allografts undergoing CAN. We investigate whether there is difference between rapamycin (Rapa) and FK506 in the expression of cytoprotective genes in rat kidney allografts undergoing CAN. METHODS: Sprague-Dawley rat renal grafts were orthotopically transplanted into Wistar rats following the procedure of Kamada with our modification. The recipients were divided into three oral treatment groups: group 1: vehicle group (cyclosporine [CsA] 10 mg/kg.dx 10 days followed by vehicle); group 2: Rapa group (CsA 10 mg/kg.d x 10 d followed by Rapa 0.8 mg/kg.d); group 3: FK506 group (CsA 10 mg/kg.d x 10 d followed by FK506 0.15 mg/kg.d). At the same times after transplantation, the rats were sacrificed to harvest the renal allografts. The expression of four cytoprotective genes, A20, heme oxygenase (HO)-1, Bcl-2, and Bcl-X/L were analyzed in these grafted kidneys by quantitative reverse transcriptase polymerase chain reaction and immunohistochemistry. RESULTS: Four cytoprotective genes were all detected in rat kidney allografts undergoing CAN. The expression of A20 in the Rapa group was significantly higher than that in the FK506 or the vehicle group (P < .05). There was no significant difference between the Rapa group and FK506 group in the expressions of HO-1, Bcl-2, and Bcl-X/L. CONCLUSIONS: We demonstrate that various immunosuppressive agents have different effects on the expression of cytoprotective genes.

Animals↗
PubMed1997

Pentadecapeptide BPC 157, cimetidine, ranitidine, bromocriptine, and atropine effect in cysteamine lesions in totally gastrectromized rats: a model for cytoprotective studies.

A superior effectiveness in various lesion assays was noted for the novel pentadecapeptide BPC 157, originated from human gastric juice protein (BPC) and claimed to be a cytoprotective agent. From this viewpoint, as a previously untreated experimental improvement to create an acid-free environmental for cytoprotection studies, total gastrectomy was done 24 hr before the ulcerogenic procedure. In the absence of stomach and gastric acid, the damaging effects of cysteamine (400 mg/kg subcutaneously, death 24 hr thereafter), to date thought to be an acid-related duodenal ulcerogen, and the BPC 157 cytoprotective effect (10 microg or 10 ng/kg intraperitoneally) were further challenged. BPC 157 was compared with reference agents [cimetidine (50), ranitidine (10), omeprazole (10), bromocriptine (10) and atropine (10) (mg/kg intraperitoneally, 1 hr before cysteamine] known to be also cytoprotective. In naive rats, with intact stomach, all of them showed a strong beneficial effect. Interestingly, in gastrectomized animals, the application of BPC 157 or the reference agents before cysteamine significantly prevented the otherwise severe duodenal lesion development noted in the control gastrectomized cysteamine rats. In groups without cysteamine, no lesions were noted (laparotomy, gastrectomy only, 24 or 48 hr postsurgical period), nor was lesion potentiation seen in cysteamine-treated laparotomized animals. In summary, these findings--equal damaging effect of cysteamine and equal protection of pentadecapeptide BPC 157 and reference agents in gastrectomized and rats with intact stomach--seem to be particularly relevant for a cytoprotective viewpoint. Without a stomach, the cysteamine damaging effect was convincingly defined as an essential gastric acid-independent injury (analogous to ethanol gastric lesions). Likewise, a high "cytoprotective capacity," apparently acid independent, common for all tested agents (novel pentadecapeptide BPC 157, cimetidine, ranitidine, omeprazole and atropine) could be clearly stressed.

Animals↗
PubMed1998

Nuclear factor kB-independent cytoprotective pathways originating at tumor necrosis factor receptor-associated factor 2.

Most normal and neoplastic cell types are resistant to tumor necrosis factor (TNF) cytotoxicity unless cotreated with protein or RNA synthesis inhibitors, such as cycloheximide and actinomycin D. Cellular resistance to TNF requires TNF receptor-associated factor 2 (TRAF2), which has been hypothesized to act mainly by mediating activation of the transcription factors nuclear factor kB (NFkB) and activator protein 1 (AP1). NFkB was proposed to switch on transcription of yet unidentified anti-apoptotic genes. To test the possible existence of NFkB-independent cytoprotective pathways, we systematically compared selective trans-dominant inhibitors of the NFkB pathway with inhibitors of TRAF2 signaling for their effect on TNF cytotoxicity. Blockade of TRAF2 function(s) by signaling-deficient oligomerization partners or by molecules affecting TRAF2 recruitment to the TNF receptor 1 complex completely abrogated the cytoprotective response. Conversely, sensitization to TNF cytotoxicity induced by a selective NFkB blockade affected only a fraction of TNF-treated cells in an apparently stochastic manner. No cytoprotective role for c-Jun amino-terminal kinases/stress-activated protein kinases (JNKs/SAPKs), which are activated by TRAF2 and contribute to stimulation of activator protein 1 activity, could be demonstrated in the cellular systems tested. Although required for cytoprotection, TRAF2 is not sufficient to protect cells from TNF + cycloheximide cytotoxicity when overexpressed in transfected cells, thus indicating an essential role of additional TNF receptor 1 complex components in the cytoprotective response. Our results indicate that TNF-induced cytoprotection is a complex function requiring the integration of multiple signal transduction pathways.

Animals↗
PubMedDate not supplied

A correlative study on the mechanism of adaptive cytoprotection against ethanol-induced gastric lesion formation in rats.

The protective effect of mild irritants against the subsequent gastric injury induced by necrotizing agents has been termed 'adaptive cytoprotection'. In this study, the possible pathway and mechanisms of adaptive cytoprotection induced by 20% ethanol were investigated. An ex-vivo gastric chamber preparation was used. The gastric mucosa was exposed to 20% ethanol before subsequent administration of 100% ethanol 15 min later. Subdiaphragmatic vagotomy or drug pretreatment was carried out in order to elucidate the mechanisms of adaptive cytoprotection by 20% ethanol. The results showed that 20% ethanol pre-exposure significantly protected the gastric mucosa against damage caused by 100% ethanol. This protective action was completely abolished by atropine or lidocaine pretreatment, whereas vagotomy and hexamethonium failed to have a significant influence. The cytoprotective effect, however, was independent of the gastric secretory volume, titratable acid content, luminal soluble mucus level and gastric mucosal blood flow. Exposure of only half the gastric mucosa to the mild irritant resulted in the protection of both sides of the mucosa. All these findings indicate that the adaptive cytoprotection of 20% ethanol involves the participation of chemoreceptors and muscarinic receptors in the gastric mucosa. An internal enteric reflex arc, with transmission of signals within the gastric mucosa, may also contribute to the cytoprotective process of the mild irritant.

Adaptation, Physiological↗
PubMed1983

Mild irritants prevent gastric necrosis through "adaptive cytoprotection" mediated by prostaglandins.

Several prostaglandins (PG) were found earlier to be cytoprotective for the stomach and the intestine. We now report that mild irritants, given intragastrically, are also cytoprotective by stimulating the release of PG by the stomach. Several "mild irritants," 10-20% ethanol, 0.2-0.35 M HCl, 0.05-0.075 M NaOH, 2-4% NaCl, and water at 70 degrees C, were given orally to fasted rats. Fifteen minutes later, one of the following necrotizing agents was administered orally: 100% ethanol, 0.6 M HCl, 0.2 M NaOH, 25% NaCl solution, and boiling water. One hour later, the stomachs were removed and necrotic lesions graded. The mild irritants inhibited the necrotic lesions dose dependently. After a single treatment, protection lasted 1 h; repeated administrations maintained cytoprotection for as long as the mild irritants were being given. Indomethacin, an inhibitor of PG synthesis, abolished cytoprotection by mild irritants. After oral administration of NaOH at cytoprotective concentrations (0.01-0.1 M), the amounts of PGE2, PGF2 alpha, and thromboxane B2 formed by the gastric mucosa increased steadily up to threefold. The protection elicited by mild irritants is called "adaptive cytoprotection." The increased synthesis of PG may represent a physiological, natural defense mechanism that may be necessary to maintain cellular integrity of the gastrointestinal mucosa, in spite of the hostile environment caused by luminal contents.

Acclimatization↗